Showing papers by "French Institute of Health and Medical Research published in 1996"
TL;DR: Mice have been generated that are transgenic for the 5' end of the human HD gene carrying CAG/polyglutamine repeat expansion that exhibits many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures.
3,056 citations
TL;DR: The last version of the Généthon human linkage map is reported, which consists of 5,264 short tandem repeat polymorphisms with a mean heterozygosity of 70%.
Abstract: The great increase in successful linkage studies in a number of higher eukaryotes during recent years has essentially resulted from major improvements in reference genetic linkage maps, which at present consist of short tandem repeat polymorphisms of simple sequences or microsatellites. We report here the last version of the Genethon human linkage map. This map consists of 5,264 short tandem (AC/TG)n repeat polymorphisms with a mean heterozygosity of 70%. The map spans a sex-averaged genetic distance of 3,699 cM and comprises 2,335 positions, of which 2,032 could be ordered with an odds ratio of at least 1,000:1 against alternative orders. The average interval size is 1.6 cM; 59% of the map is covered by intervals of 2 cM at most and 1% remains in intervals above 10 cM.
2,982 citations
TL;DR: It is shown that a mutant allele of CCR-5 is present at a high frequency in caucasian populations, but is absent in black populations from Western and Central Africa and Japanese populations, and a 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains.
Abstract: HIV-1 and related viruses require co-receptors, in addition to CD4, to infect target cells. The chemokine receptor CCR-5 (ref.1) was recently demonstrated to be a co-receptor for macrophage-tropic (M-tropic) HIV-1 strains, and the orphan receptor LESTR (also called fusin) allows infection by strains adapted for growth in transformed T-cell lines (T-tropic strains). Here we show that a mutant allele of CCR-5 is present at a high frequency in caucasian populations (allele frequency, 0.092), but is absent in black populations from Western and Central Africa and Japanese populations. A 32-base-pair deletion within the coding region results in a frame shift, and generates a non-functional receptor that does not support membrane fusion or infection by macrophage- and dual-tropic HIV-1 strains. In a cohort of HIV-1 infected caucasian subjects, no individual homozygous for the mutation was found, and the frequency of heterozygotes was 35% lower than in the general population. White blood cells from an individual homozygous for the null allele were found to be highly resistant to infection by M-tropic HIV-1 viruses, confirming that CCR-5 is the major co-receptor for primary HIV-1 strains. The lower frequency of heterozygotes in seropositive patients may indicate partial resistance.
2,668 citations
TL;DR: Ten cases of Creutzfeldt-Jakob disease have been identified in the UK in recent months with a new neuropathological profile that raises the possibility that they are causally linked to BSE.
2,574 citations
TL;DR: A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.
Abstract: Friedreich's ataxia (FRDA) is an autosomal recessive, degenerative disease that involves the central and peripheral nervous systems and the heart. A gene, X25, was identified in the critical region for the FRDA locus on chromosome 9q13. This gene encodes a 210-amino acid protein, frataxin, that has homologs in distant species such as Caenorhabditis elegans and yeast. A few FRDA patients were found to have point mutations in X25, but the majority were homozygous for an unstable GAA trinucleotide expansion in the first X25 intron.
2,552 citations
TL;DR: It is demonstrated that FGF 1 is the only FGF that can activate all FGF receptor splice variants and the relative activity of all the other members of the FGF family is determined.
2,066 citations
TL;DR: The characterization of the human Notch3 gene, which was previously mapped to the CADASIL critical region, is reported, indicating that Notch 3 could be the defective protein in CADASil patients.
Abstract: Stroke is the third leading cause of death, and vascular dementia the second cause of dementia after Alzheimer's disease. CADASIL (for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) causes a type of stroke and dementia whose key features include recurrent subcortical ischaemic events and vascular dementia and which is associated with diffuse white-matter abnormalities on neuroimaging. Pathological examination reveals multiple small, deep cerebral infarcts, a leukoencephalopathy, and a non-atherosclerotic, non-amyloid angiopathy involving mainly the small cerebral arteries. Severe alterations of vascular smooth-muscle cells are evident on ultrastructural analysis. We have previously mapped the mutant gene to chromosome 19. Here we report the characterization of the human Notch3 gene which we mapped to the CADASIL critical region. We have identified mutations in CADASIL patients that cause serious disruption of this gene, indicating that Notch3 could be the defective protein in CADASIL patients.
1,917 citations
TL;DR: The measurement of AOPP is proposed as a reliable marker to estimate the degree of oxidant-mediated protein damage in uremic patients and to predict the potential efficacy of therapeutic strategies aimed at reducing such an oxidative stress.
1,730 citations
TL;DR: Five‐year survival rates after resection of liver metastases from colorectal carcinoma are close to 25%, and selection of patients likely to benefit from surgery remains controversial and subjective.
Abstract: BACKGROUND
Five-year survival rates after resection of liver metastases from colorectal carcinoma are close to 25%. Recurrences occur in two-thirds of the patients after surgery. Selection of patients likely to benefit from surgery remains controversial and subjective.
METHODS
Data from 1568 patients with resected liver metastases from colorectal carcinoma were collected. The prognostic value of different factors was studied through uni- and multivariate analyses. A scoring system was developed including the most relevant factors.
RESULTS
Two- and 5-year survival rates were 64% and 28%, respectively, and were affected by: age; size of largest metastasis or CEA level; stage of the primary tumor; disease free interval; number of liver nodules; and resection margin. Giving one point to each factor, the population was divided into three risk groups with different 2-year survival rates: 0–2 (79%), 3–4 (60%), 5–7 (43%).
CONCLUSIONS
A simple prognostic scoring system was proposed to evaluate the chances for cure of patients after resection of liver metastases from colorectal carcinoma. The comparison between expected survival and estimated operative risk can help determine on an objective basis whether surgery is worthwhile. This system needs further prospective validation. Cancer 1996;77:1254-62.
1,652 citations
TL;DR: Investigation of the behavioural effects of morphine reveals that a lack of μ receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence, and concludes that the µ-opioid-receptor gene product is a mandatory component of the opioid system for morphine action.
Abstract: Despite tremendous efforts in the search for safe, efficacious and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Opioids exert their pharmacological actions through three opioid-receptor classes, mu, delta and kappa, whose genes have been cloned. Genetic approaches are now available to delineate the contribution of each receptor in opioid function in vivo. Here we disrupt the mu-opioid-receptor gene in mice by homologous recombination and find that there are no overt behavioural abnormalities or major compensatory changes within the opioid system in these animals. Investigation of the behavioural effects of morphine reveals that a lack of mu receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. We observed no behavioural responses related to delta- or kappa-receptor activation with morphine, although these receptors are present and bind opioid ligands. We conclude that the mu-opioid-receptor gene product is the molecular target of morphine in vivo and that it is a mandatory component of the opioid system for morphine action.
1,641 citations
TL;DR: Results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.
Abstract: MUTATIONS in the genes encoding amyloid-β precursor protein (APP)1 presenilin 1 (PS1)2 and presenilin 2 (PS2)3,4 are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid β-protein (βAPP) processing, which normally leads to the secretion of amyloid-β protein (relative molecular mass 4,000; Mr 4K; ∼90% Aβ1–40, ∼10% Aβ1–42(43)), so that the extracellular concentration of Aβ42(43) is increased5. This increase in Aβ42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because Aβ42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of Aβ42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain Aβ42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.
TL;DR: This work tested the stimulus specificity of high-frequency oscillations in humans using three types of visual stimuli: two coherent stimuli (a Kanizsa and a real triangle) and a noncoherent stimulus (“no-triangle stimulus”).
Abstract: Considerable interest has been raised by non-phase-locked episodes of synchronization in the gamma-band (30-60 Hz). One of their putative roles in the visual modality is feature-binding. We tested the stimulus specificity of high-frequency oscillations in humans using three types of visual stimuli: two coherent stimuli (a Kanizsa and a real triangle) and a noncoherent stimulus ("no-triangle stimulus"). The task of the subject was to count the occurrences of a curved illusory triangle. A time-frequency analysis of single-trial EEG data recorded from eight human subjects was performed to characterize phase-locked as well as non-phase-locked high-frequency activities. We found in early phase-locked 40 Hz component, maximal at electrodes Cz-C4, which does not vary with stimulation type. We describe a second 40 Hz component, appearing around 280 msec, that is not phase-locked to stimulus onset. This component is stronger in response to a coherent triangle, whether real or illusory: it could reflect, therefore, a mechanism of feature binding based on high-frequency synchronization. Because both the illusory and the real triangle are more target-like, it could also correspond to an oscillatory mechanism for testing the match between stimulus and target. At the same latencies, the low-frequency evoked response components phase-locked to stimulus onset behave differently, suggesting that low- and high-frequency activities have different functional roles.
TL;DR: A picture has emerged depicting the classic endocrine control of ovarian function by LH and FSH, entangled in a maze of regulatory systems hinging on cell-cell interactions between follicular cells, via action of a variety of molecules.
Abstract: I. Introduction IN THE adult ovary, folliculogenesis starts when follicles leave the pool of resting follicles (RF) to enter the growth phase. From there, the early growing follicle undergoes a developmental process including a dramatic course of cellular proliferation and differentiation. In primates, only one follicle commonly reaches the preovulatory stage every cycle; most follicles fail to complete this maturation scheme, dying in the process termed atresia. In recent years, a picture has emerged depicting the classic endocrine control of ovarian function by LH and FSH, entangled in a maze of regulatory systems hinging on cell-cell interactions between follicular cells, via action of a variety of molecules (1–3). Different types of cell-cell interactions have been described. In paracrine regulations, a molecule synthesized by one cellular type is released into the interstitial milieu to act directly on another cellular type. In autocrine regulations, molecules synthesized by one cellular type are rel...
Eugenia E. Calle1, Clark W. Heath1, H. L. Miracle-McMahill1, R. J. Coates2 +185 more•Institutions (41)
TL;DR: Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies as mentioned in this paper.
TL;DR: The identification of human Sonic Hedgehog (SHH) as HPE3 — the first known gene to cause HPE is reported, and five families that segregate different heterozygous SHH mutations are found that predict premature termination of the SHH protein.
Abstract: Holoprosencephaly (HPE) is a common developmental defect of the forebrain and frequently the midface in humans, with both genetic and environmental causes HPE has a prevalence of 1:250 during embryogenesis and 1:16,000 newborn infants, and involves incomplete development and septation of midline structures in the central nervous system (CNS) with a broad spectrum of clinical severity Alobar HPE, the most severe form which is usually incompatible with postnatal life, involves complete failure of division of the forebrain into right and left hemispheres and is characteristically associated with facial anomalies including cyclopia, a primitive nasal structure (proboscis) and/or midfacial clefting At the mild end of the spectrum, findings may include microcephaly, mild hypotelorism, single maxillary central incisor and other defects (Fig 1) This phenotypic variability also occurs between affected members of the same family The molecular basis underlying HPE is not known, although teratogens, non-random chromosomal anomalies and familial forms with autosomal dominant and recessive inheritance have been described HPE3 on chromosome 7q36 is one of at least four different loci implicated in HPE Here, we report the identification of human Sonic Hedgehog (SHH) as HPE3-the first known gene to cause HPE Analyzing 30 autosomal dominant HPE (ADHPE) families, we found five families that segregate different heterozygous SHH mutations Two of these mutations predict premature termination of the SHH protein, whereas the others alter highly conserved residues in the vicinity of the alpha-helix-1 motif or signal cleavage site
TL;DR: It is demonstrated that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-α) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity, which supports the hypothesis that GDNF uses a multi-subunit receptor system in which GDN FR-α and Ret function as the ligand-binding and signalling components.
Abstract: Glial-cell-line-derived neurotrophic factor (GDNF) is a potent survival factor for central and peripheral neurons, and is essential for the development of kidneys and the enteric nervous system. Despite the potential clinical and physiological importance of GDNF, its mechanism of action is unknown. Here we show that physiological responses to GDNF require the presence of a novel glycosyl-phosphatidylinositol (GPI)-linked protein (designated GDNFR-alpha) that is expressed on GDNF-responsive cells and binds GDNF with a high affinity. We further demonstrate that GDNF promotes the formation of a physical complex between GDNFR-alpha and the orphan tyrosin kinase receptor Ret, thereby inducing its tyrosine phosphorylation. These findings support the hypothesis that GDNF uses a multi-subunit receptor system in which GDNFR-alpha and Ret function as the ligand-binding and signalling components, respectively.
TL;DR: Ultrasonographic measurements of the os calcis predict the risk of hip fracture in elderly women living at home as well as DPXA of the hip does, and the combination of both methods makes possible the identification of women at very high or very low risk of fracture.
TL;DR: The clinical spectrum of Friedreich's ataxia is broader than previously recognized, and the direct molecular test for the GAA expansion on chromosome 9 is useful for diagnosis, determination of prognosis, and genetic counseling.
Abstract: Background Friedreich's ataxia, the most common inherited ataxia, is associated with a mutation that consists of an unstable expansion of GAA repeats in the first intron of the frataxin gene on chromosome 9, which encodes a protein of unknown function. Methods We studied 187 patients with autosomal recessive ataxia, determined the size of the GAA expansions, and analyzed the clinical manifestations in relation to the number of GAA repeats and the duration of disease. Results One hundred forty of the 187 patients, with ages at onset ranging from 2 to 51 years, were homozygous for a GAA expansion that had 120 to 1700 repeats of the trinucleotides. About one quarter of the patients, despite being homozygous, had atypical Friedreich's ataxia; they were older at presentation and had intact tendon reflexes. Larger GAA expansions correlated with earlier age at onset and shorter times to loss of ambulation. The size of the GAA expansions (and particularly that of the smaller of each pair) was associated with the ...
TL;DR: It is concluded that neuromuscular and visual impairments, as well as femoral-neck BMD, are significant and independent predictors of the risk of hip fracture in elderly mobile women, and that their combined assessment improves the prediction of hip fractures.
TL;DR: Neuropsychological investigations of patients with Parkinson’s disease have shown specific impairments even in the early stages of the disease, which include deficit of behavioural regulation in sorting or planning tasks, defective use of memory stores, and impaired manipulation of internal representation of visuospatial stimuli, suggesting a functional continuity or complementarity between the basal ganglia and association areas of the prefrontal cortex.
Abstract: Neuropsychological investigations of patients with Parkinson's disease have shown specific impairments even in the early stages of the disease, which include deficit of behavioural regulation in sorting or planning tasks, defective use of memory stores, and impaired manipulation of internal representation of visuospatial stimuli. These deficits, reported in a disease which predominantly involves subcortical structures, have drawn attention to a potential role of the basal ganglia in cognitive processes. Given the modulatory role of the basal ganglia, these disorders might result from more fundamental deficits concerning the allocation of attentional resources, the temporal organization of behaviour, the maintenance of representations in working memory or the self-elaboration of internal strategies, all of which resemble dysfunctions of processes that are commonly considered to be controlled by the frontal lobes. This suggests a functional continuity or complementarity between the basal ganglia and association areas of the prefrontal cortex. The recent description in primates of segregated loops that interconnect discrete regions of the caudate nucleus to the dorsolateral and orbitofrontal regions of the prefrontal cortex via the thalamus may give some support to this hypothesis. Alternatively, degeneration of the ascending cholinergic and catecholaminergic neuronal systems may contribute, at least in part, to the occurrence of this frontal-lobe-like symptomatology associated with Parkinson's disease.
TL;DR: A spontaneous mouse model of RA is described, generated fortuitously by crossing a T cell receptor (TCR) transgenic line with the NOD strain, and it is suggested that human RA develops by an analogous mechanism.
TL;DR: It is reported the first identification of a cellular receptor mediating entry of a gram-positive bacterium into nonphagocytotic cells by an affinity chromatography approach, and reveals a novel type of heterophilic interactions for E-cadherin.
TL;DR: The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglUTamine expansion diseases.
Abstract: Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.
TL;DR: Patients with lesions restricted to the parietal cortex were found to be impaired selectively at predicting, through mental imagery, the time necessary to perform differentiated finger movements and visually guided pointing gestures, in comparison to normal individuals and to a patient with damage to the primary motor area.
Abstract: Recent neuroimagery findings showed that the patterns of cerebral activation during the mental rehearsal of a motor act are similar to those produced by its actual execution. This concurs with the notion that part of the distributed neural activity taking place during movement involves internal simulations, but it is not yet clear what specific contribution the different brain areas involved bring to this process. Here, patients with lesions restricted to the parietal cortex were found to be impaired selectively at predicting, through mental imagery, the time necessary to perform differentiated finger movements and visually guided pointing gestures, in comparison to normal individuals and to a patient with damage to the primary motor area. These results suggest that the parietal cortex is important for the ability to generate mental movement representations.
TL;DR: The mitochondrial defect identified in HD caudate parallels that induced by HD neurotoxin models and further supports the role of abnormal energy metabolism in HD.
Abstract: Although the Huntington's disease (HD) gene defect has been identified, the structure and function of the abnormal gene product and the pathogenetic mechanisms involved in producing death of selective neuronal populations are not understood. Indirect evidence from several sources indicates that a defect of energy metabolism and consequent excitotoxicity are involved in HD. Toxin models of HD may be induced by 3-nitropropionic acid or malonate, both inhibitors of succinate dehydrogenase, complex II of the mitochondrial respiratory chain. We analyzed mitochondrial respiratory chain function in the caudate nucleus (n = 10) and platelets (n = 11) from patients with HD. In the caudate nucleus, severe defects of complexes II and III (53-59%, p < 0.0005) and a 32-38% (p < 0.01) deficiency of complex IV activity were demonstrated. No deficiencies were found in platelet mitochondrial function. The mitochondrial defect identified in HD caudate parallels that induced by HD neurotoxin models and further supports the role of abnormal energy metabolism in HD. The relationship of the mitochondrial defect to the role of huntingtin is not known.
TL;DR: The goal of this overview is to show that pressure is a powerful tool for the study of proteins and modulation of enzymatic activity.
Abstract: Many biochemists would regard pressure as a physical parameter mainly of theoretical interest and of rather limited value in experimental biochemistry. The goal of this overview is to show that pressure is a powerful tool for the study of proteins and modulation of enzymatic activity.
TL;DR: Physiological evidence from measurements of regional brain activity and of autonomic responses in normal subjects and behavioral observations from brain damaged patients are reviewed to propose that motor imagery shares neural mechanisms with processes used in motor control.
TL;DR: It is shown that myelination can be inhibited by blocking the action potential of neighboring axons or enhanced by increasing their electrical activity, clearly linking neuronal electrical activity to myelinogenesis.
Abstract: The oligodendrocyte is the myelin-forming cell in the central nervous system. Despite the close interaction between axons and oligodendrocytes, there is little evidence that neurons influence myelinogenesis. On the contrary, newly differentiated oligodendrocytes, which mature in culture in the total absence of neurons, synthesize the myelin-specific constituents of oligodendrocytes differentiated in vivo and even form myelin-like figures. Neuronal electrical activity may be required, however, for the appropriate formation of the myelin sheath. To investigate the role of electrical activity on myelin formation, we have used highly specific neurotoxins, which can either block (tetrodotoxin) or increase (alpha-scorpion toxin) the firing of neurons. We show that myelination can be inhibited by blocking the action potential of neighboring axons or enhanced by increasing their electrical activity, clearly linking neuronal electrical activity to myelinogenesis.
TL;DR: In this article, the authors reported an alternative mechanism of NF-κB activation by using tyrosine-phosphorylation of IκB-α in the presence of pervanadate.
TL;DR: This paper addresses the issue of the functional correlates of motor imagery, using mental chronometry, monitoring the autonomic responses and measuring cerebral blood flow in humans to provide converging support for the hypothesis that imagined and executed actions share, to some extent, the same central structures.